Several different lines of evidence suggest that the dopamine 3 (D3) subtype receptor may be involved in the positive rewarding mechanism of the addiction of several drugs, including cocaine, D-amphetamine and other psychostimulants. Recent studies also strongly indicate that selective D3 ligands may have the therapeutic potential as novel pharmacotherapies for the treatment of cocaine addiction, abuse and dependence. Although a number of selective D3 ligands have been reported, most of them have insufficient solubility to be evaluated in vivo and to be developed as potentially useful therapeutic agents. Furthermore, while some D3 ligands show high affinity at the D3 receptor and excellent selectivity over the D2 receptor and other dopamine receptor subtypes based upon their in vitro data, they display very limited selectivity for the D3 receptor over the D2 receptor in our well validated in vivo functional assays in the rat. Hence, potent D3 ligands with high in vitro and in vivo selectivity and favorable physiochemical and pharmacological properties are clearly needed for further elucidation of the role of the D3 receptor in drug addiction and more importantly for the development of a new therapy for the treatment of cocaine abuse through modulation of the D3 receptor. In this project, we propose to design and synthesize potent and highly selective D3 ligands with favorable physiochemical and pharmacological properties and to perform detailed in vitro and in vivo evaluations for their potency, specificity and function at the D3 receptor and their therapeutic potential for the treatment of cocaine abuse. Our preliminary data have clearly demonstrated that it is feasible to design potent and highly selective D3 ligands with excellent drug like properties for drug development. Our long-term goal is to develop a potent and highly selective D3 ligand for the treatment of cocaine abuse. To achieve this goal, we have assembled a multi-disciplinary team consisting of investigators with extensive expertise in computational drug design and medicinal chemistry, biochemical pharmacology of the dopamine receptors, in vivo behavioral pharmacology and drug metabolism and pharmacokinetics (DMPK). Successfully carried out, our research will advance at least one highly promising D3 ligand into advanced preclinical development as a novel pharmacotherapy for addiction, dependence and abuse of cocaine.